S.a SPECIFIC AIMS The overarching goal for the proposed Network for Translations! Research (NTR) Center is to translate a novel real-time noninvasive multimodal clinical imaging tool into clinical practice for sentinel lymph node (SLN) mapping. The proposed imaging tool is a hybrid technology, referred to as photoacoustic tomography (PAT), to be used in combination with conventional ultrasound imaging (ultrasonography). Ultrasound imaging will be used to image lymph nodeswhich are hypoechoic, whereas PAT will be used to identify whether a node is sentinel (the first draining node) by detecting the accumulated methylene blue dye. Ultrasound imaging cannot detect methylene blue dye because the dye has little mechanical contrast. In comparison, PAT has demonstrated high sensitivity in detecting methylene blue dye because the dye has high optical contrast. In other words, while ultrasound imaging provides structural information, PAT provides functional information about the lymphatics. In addition, the task-specific projects will enhance functional PAT in several aspects, especially, in molecular imaging of metastases. Sentinel lymph node biopsy (SLNB) has become the standard method of axillary staging for patients with breast cancer and clinically negative axillae. Even though SLNB using both methylene blue dye and radioactive tracers (Tc-99 colloids) has a high identification rate, it still relies on an invasive surgical procedure with associated morbidity. Axillary ultrasound has emerged as a diagnostic tool to evaluate the axilla, but it can only assess morphology and cannot specifically identify the SLN. The ability to identify the SLN noninvasively in vivo would be a highly useful clinical tool for breast cancer patients, as it would enable the clinician to identify the SLN in vivo so that non-invasive diagnostic methods (e.g., fine needle aspiration biopsy and reverse transcription polymerase chain reaction) could be utilized to stage the axilla without the morbidity of an operative procedure. The proposed multimodal technology can potentially map SLN noninvasively with high spatial resolution in real time yet without the use of radioactive tracers; consequently, invasive surgical procedures are avoided. Furthermore, photoacoustic molecular imaging can potentially identify metastases in situwithout even needle biopsyand monitor therapy as well. Therefore, the proposed multi-modal photoacoustic/ultrasound imaging technology has high potential impact on breast axillary staging and management. We hypothesize that PAT can reliably map SLNs, which accumulate methylene blue dye. Methylene blue dye is in routine clinical use and is an excellent optical contrast agent for PAT. Its peak absorption wavelength is 690 nm, which lies near the optimal optical penetration window. Therefore, imaging SLNs is a perfect clinical application of PAT. PAT is based on the generation of photoacoustic waves by safely depositing short-pulsed optical energy into tissue. Each laser pulse causes a rapid temperature rise usually on the order of 10 millidegrees. The ultrasonic emission due to thermoelastic expansion is detected with an array of ultrasonic transducers and then used to reconstruct an image. The PAT technology is designed to overcome the poor spatial resolution of pure optical imaging yet to retain the high optical contrasts. In terms of spatial resolution, pure optical imaging suffers from strong optical scattering in tissue. By contrast, ultrasonic waves can propagate in tissue with relatively low scattering and can therefore provide good spatial resolution. The applicants have demonstrated speckle-free photoacoustic images at high spatial resolution. Therefore, PAT integrates high optical contrast with high ultrasonic resolution in a single hybrid imaging modality.